The number of patients in Japan with arteriosclerosis and hyperlipemia, which are associated with a high risk of high-mortality diseases such as myocardial infarction and cerebral apoplexy, is said to be as many as thirty million, including subjects having no subjective symptoms. Even at the present time, after the Guidelines for Prevention of Atherosclerotic Cardiovascular Diseases have been revised by the Japan Atherosclerosis Society, such diseases rank high among the causes of death in Japan. Arteriosclerosis and hyperlipemia are significant health problems not only in Japan but also in Europe and the Americas.
The drugs that are primarily used at present for prevention and treatment of arteriosclerosis and/or hyperlipemia are statin drugs, which specifically inhibit hydroxy-3-methylglutaryl coenzyme A (Co-A) (hereinafter abbreviated as HMG-CoA) reductase. Statin drugs were among the best-selling drugs in the world for 8 consecutive years, starting in 2001. These drugs are widely used, as demonstrated by the fact that two statin drugs ranked among the top thirty drugs having the highest worldwide sales in 2008.
In fact, however, it has been found that statin drugs affect the prevention of onset in only 30% to 40% of patients, and these drugs do not suppress cardiovascular diseases or the like in about half of patients who have received therapy with them (Non-Patent Document 1). The reasons why HMG-CoA reductase inhibitors, such as statin drugs, which are currently used as prophylactic or therapeutic agents for arteriosclerosis, cannot sufficiently suppress cardiovascular diseases or similar diseases are considered to relate to the fact that the mechanism of onset of arteriosclerosis is complicated. Often, arteriosclerosis is considered to develop due to various factors, such as heredity factors, disease history of diabetes or the like, or drug ingestion history, acting in combination. Therefore, diagnosis and treatment should be performed in accordance with the pathological conditions of each patient, so as to prevent or treat arteriosclerosis and/or hyperlipemia. Accordingly, there is an urgent need for the development of a pharmaceutical product having a new mechanism that is different from the mechanism of statin drugs and can be expected to have effects of suppressing the onset of disorders in the coronary artery and/or degenerating lesions in the coronary artery.
Cholesterol acyltransferase (hereinafter abbreviated as ACAT) is expected to serve as a target for a preventive and therapeutic agent for arteriosclerosis and/or hyperlipemia having a new mechanism (Non-Patent Document 2). ACAT is an enzyme that introduces an acyl group into cholesterol. A number of synthetic ACAT inhibitors have heretofore been developed. However, these inhibitors have not yet been put to clinical use due to side effects or insufficient effects (Non-Patent Document 3).
It has recently been revealed that ACAT exists in the form of two isozymes, ACAT1 and ACAT2, which have different in vivo functions and different locations from each other (Non-Patent Document 4). ACAT1 is widely found in many living cells and tissues and is highly expressed particularly in macrophages and smooth muscle cells. Also, ACAT1 is known to cause the formation of foam macrophage cells causing arteriosclerosis on the artery wall. In contrast, ACAT2 is expressed specifically in the small intestine or liver. ACAT2 is considered to be involved in the absorption of dietary cholesterol and the secretion of very low-density lipoproteins in each of these organs.
As described above, ACAT1 and ACAT2 were found to be different with respect to in vivo functions. In the development of new drugs targeting ACAT, accordingly, it is critical to identify the selectivity of ACAT1 and that of ACAT2. For example, synthetic ACAT inhibitors, the development of which had been abandoned, were found to have activity of selectively inhibiting ACAT1 (e.g., Wu-V-23 and K-604) or inhibiting both ACAT1 and ACAT2 isozymes (e.g., avasimibe and pactimibe) (Non-Patent Document 5). Development of such synthetic ACAT inhibitors had been abandoned due to side effects, and ACAT1 knockout mice had developed side effects in the past (Non-Patent Documents 6 and 7). On the contrary, ACAT2 knockout mice exhibited effects of anti-arteriosclerosis (Non-Patent Document 8). As preventive/therapeutic agents against arteriosclerosis and/or hyperlipemia (including lipemia, fatty liver, and obesity), accordingly, the development of drugs from a selective inhibitor against ACAT2, which is an ACAT isozyme, has been strongly desired (Non-Patent Document 9).
As selective ACAT2 inhibitors, a naturally occurring organic compound (that is, pyripyropene A) (Non-Patent Document 10) and pyripyropene A derivatives obtained from pyripyropene A via a semi-synthetic technique (Patent Documents 1 to 3) were found. In addition, anti-arteriosclerotic effects in liver ACAT2 knockout mice achieved with an antisense oligonucleotide (Non-Patent Document 11), anti-arteriosclerotic effects resulting from animal experiments using pyripyropene A (Non-Patent Document 12), and the results of total synthesis of pyripyropene A (Non-Patent Document 13) were reported.